G-protein-coupled receptors (GPCRs) are the molecular target of 40% of marketed drugs and the most investigated structures to develop novel therapeutics. Different members of the GPCRs superfamily can modulate the same cellular process acting on diverse pathways, thus representing an attractive opportunity to achieve multitarget drugs with synergic pharmacological effects. Here, we present a series of compounds with dual activity toward cysteinyl leukotriene receptor 1 (CysLT₁R) and G-protein-coupled bile acid receptor 1 (GPBAR1). They are derivatives of REV5901─the first reported dual compound─with therapeutic potential in the treatment of colitis and other inflammatory processes. We report the binding mode of the most active compounds in the two GPCRs, revealing unprecedented structural basis for future drug design studies, including the presence of a polar group opportunely spaced from an aromatic ring in the ligand to interact with Arg79^2.60 of CysLT₁R and achieve dual activity.

中文翻译：

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开发作用于半胱氨酰白三烯受体 1 和 G 蛋白偶联胆汁酸受体 1 的多靶点化合物的结构基础

G 蛋白偶联受体 (GPCR) 是 40% 的已上市药物的分子靶标，也是开发新疗法的研究最多的结构。GPCRs 超家族的不同成员可以调节作用于不同途径的相同细胞过程，因此代表了实现具有协同药理作用的多靶点药物的有吸引力的机会。在这里，我们提出了一系列对半胱氨酰白三烯受体 1 (CysLT _{1 ) 具有双重活性的化合物。}R) 和 G 蛋白偶联胆汁酸受体 1 (GPBAR1)。它们是 REV5901 的衍生物——第一个报道的双重化合物——在治疗结肠炎和其他炎症过程中具有治疗潜力。我们报告了两种 GPCR 中最活跃的化合物的结合模式，为未来的药物设计研究揭示了前所未有的结构基础，包括存在与配体中的芳环适当间隔的极性基团以与CysLT ₁ R的 Arg79 ^2.60相互作用并实现双重活动。